Evaluation of the effectiveness of surgical resection and ablation for the treatment of early‐stage hepatocellular carcinoma: A retrospective cohort study

Abstract Background The optimal treatment strategy for early‐stage hepatocellular carcinoma (HCC) remains controversial, specifically in regard to surgical resection (SR) and ablation. The aim of this study was to investigate the impact of SR and ablation on recurrence and prognosis in early‐stage HCC patients, to optimize treatment strategies and improve long‐term survival. Methods A retrospective analysis was conducted on 801 patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage 0/A HCC and treated with SR or ablation between January 2015 and December 2019. The effectiveness and complications of both treatments were analyzed, and patients were followed up to measure recurrence and survival. Propensity score matching (PSM) was employed to increase comparability between the two groups. The Kaplan–Meier method was used to analyze recurrence and survival, and a Cox risk proportional hazard model was used to identify risk factors that affect recurrence and surviva. Results Before PSM, the overall survival (OS) rates were similar in both groups, with recurrence‐free survival (RFS) rates better in the SR group than in the ablation group. After PSM, there was no significant difference in OS between the two groups. However, the RFS rates were significantly better in the SR group than in the ablation group. The ablation group exhibited superior outcomes compared to the SR group, with shorter treatment times, reduced bleeding, shorter hospital stays, and lower hospital costs. Concerning the location of the HCC within the liver, comparable efficacy was observed between SR and ablation for disease located in the noncentral region or left lobe. However, for HCCs located in the central region or right lobe of the liver, SR was more effective than ablation. Conclusions This study revealed no significant difference in OS between SR and ablation for early‐stage HCC, with SR providing better RFS and ablation demonstrating better safety profiles and lower hospital costs. These findings offer valuable insights for clinicians in determining optimal treatment strategies for early‐stage HCC patients, particularly in terms of balancing efficacy, safety, and cost considerations.

7][8] Nevertheless, challenges such as the scarcity of donor livers, the intricate nature of liver transplantation, a notable incidence of postoperative complications, and elevated costs have impeded the widespread adoption of liver transplantation.Consequently, surgical resection (SR) and ablation have become the most frequently used treatments for early-stage HCC.
7][18][19][20][21][22][23][24] Most prior RCTs and retrospective studies have suffered from small sample sizes and inadequate follow-up.Additionally, the majority of studies have concentrated on comparing the outcomes of SR and ablation for HCCs less than 3 cm, with fewer investigations comparing the two treatments for tumors exceeding 3 cm and for HCCs located in different regions of the liver.
Hence, we conducted a retrospective study that included subgroup analyses of patients with HCC up to 5 cm in length and patients with different tumor sites (central or peripheral HCC, left HCC, or right HCC) to comprehensively compare the long-term survival and recurrence rates associated with resection and ablation.To mitigate the influence of confounding factors, propensity score matching (PSM) was used to analyze the baseline characteristics of the patients in the study cohorts.

| Patients
A retrospective analysis was conducted on 801 patients diagnosed with BCLC stage 0/A HCC at a single hospital between January 2015 and December 2019.Patients who underwent either SR or ablation were included in the study if they met certain criteria: (1) ≥18 years of age; (2) initial HCC diagnosis confirmed by pathological evidence or EASL guidelines (2018 edition), 6 with diagnosis in the absence of biopsy evidence primarily based on ultrasound or enhanced spiral computed tomography (CT) or magnetic resonance imaging (MRI); (3) liver function Child-Pugh grade A/B; and (4) no visible portal/hepatic vein invasion or distant metastases.The exclusion criteria included a history of previous HCC treatment, such as surgery, ablation, transarterial chemoembolization, radiotherapy, chemotherapy, immunotherapy, or targeted drug therapy; a history of other malignancies in the last 5 years; no postoperative follow-up or follow-up of less than 6 months; and missing key information, such as clinical and laboratory data.The complete screening procedure is detailed in Figure 1.Baseline patient information, including demographic data, potential causes of HCC, laboratory test data, and tumor-related imaging data, was collected.
Treatment-related information, such as perioperative conditions, complications, length of hospital stay, and costs, was recorded.Follow-up was conducted via inpatient/outpatient information every 3-6 months for the first 2 years after surgery and every 6-12 months thereafter until the end of the study.Postoperative recurrence, follow-up treatment, and HCC survival were recorded.The end of follow-up was December 31, 2022, and the primary endpoint event was overall survival, with recurrence rate and recurrence-free survival as secondary endpoint events.The study was approved by the Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University.

| Diagnosis and definition
The present study validated the diagnosis of hepatocellular carcinoma through histopathology analysis in subjects subjected to surgical resection and through pathology or diagnostic criteria in accordance with the 2018 edition of the EASL guidelines 6 in subjects subjected to ablation.For the purposes of this investigation, early-stage HCC was defined as encompassing BCLC stage 0/A.Specifically, BCLC stage 0 is characterized by a solitary tumor of ≤2 cm in diameter, while BCLC stage A entails a solitary or multiple tumors each of ≤3 cm in diameter, according to the 2022 edition of the Barcelona guidelines.

| Statistics
The present study utilized SPSS 25.0 and GraphPad Prism 7.0 for performing the statistical analyses.PSM was employed to mitigate the impacts of confounding and selection bias, with known or assumed confounders being used as dependent variables (such as age, sex, viral infections, cirrhosis, family history, combined chronic diseases, BMI, WBC, HGB, PLT, AST, ALB, TB, AFP, Child-Pugh classification, number of tumors, and tumor diameter) to match enrolled patients using the 1:1 nearest neighbor matching method (matching tolerance of 0.02).Continuous variables that met the normal distribution assumption were subjected to t tests, while those that did not conform were subjected to Mann-Whitney U tests.Categorical variables are represented as composition ratios and were subjected to either Chi-square or Fisher's exact tests to determine differences.Overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups using Kaplan-Meier and log-rank tests, and the prognostic importance of each variable for predicting OS and RFS was assessed via univariate and multivariate Cox proportional hazards regression models.Variables with p < .05according to the univariate analysis were included in the multivariate analysis, and the results are reported as risk ratios (HRs) with 95% confidence intervals (CIs).A p value <.05 was considered indicative of statistical significance.
F I G U R E 1 Flow chart of the study design.
To ensure comparability between the two groups, PSM was performed to balance the distribution of baseline variables.Ultimately, 189 patients were included in each group following PSM.The results indicated no significant differences in baseline information between the two groups ( p > .05)(Table S1).

| Ablation therapy produced superior shortterm treatment outcomes
Following PSM, the comparative analysis of perioperative outcomes between the ablation group and the SR group revealed notable differences in several perioperative parameters.Specifically, compared with the ablation group, the SR group exhibited significantly greater blood loss (100 vs. 0 mL, p < .001), a significantly greater intraoperative transfusion rate (21.2% vs. 9.0%, p < .001),and greater postoperative analgesia requirements (86.2% vs. 3.7%, p < .001).Conversely, the ablation group demonstrated a significantly shorter median operative time (3.0 vs. 1.5 h, p < .001)and median hospital stay (17 days vs. 14 days, p < .001)and lower hospital costs (57347.1 yuan vs. 42, 100.6 yuan, p < .001)than the SR group (Table 2).Postoperative complications were assessed utilizing the Dindo-Demartines-Clavien classification. 25Notably, the incidence of Grade II or higher complications was significantly greater in the SR group than in the ablation group (14.8% vs. 6.3%, p = .011)(Table S2).
In the SR group, the primary complications included lung infection

| Comparable overall survival rates were observed in patients who underwent surgical resection and ablation treatment
Prior to PSM, the cohort exhibited a median follow-up time of 61.2 months, and the median overall survival was indeterminate in both groups.Throughout the follow-up period, a total of 100 patients died, resulting in overall mortality rates of 11.7% (48/410) and 13.2% (52/391) in the respective groups.The OS rates at 1, 3, and 5 years were 98.5%, 92.9%, and 88.2%, respectively, in the SR group and 99.2%, 91.5%, and 86.7%, respectively, in the ablation group; moreover, no notable difference in OS rates was observed between the groups (HR = 0.8422, 95% CI = 0.5689-1.247;p = .3901)(Figure 2a).After PSM, the median follow-up time was 61.5 months.

| RFS was greater in patients who underwent surgical resection than in those who underwent ablation
The median follow-up duration was 53.5 months prior to PSM.In the SR group, the median RFS was not reached, while in the ablation group, the median RFS was 46 months.The overall recurrence rates  S3).Concerning the optimal treatment and prognosis following recurrence, follow-up continues with the aim of gathering extended-term survival information.

| RFS superior in surgical resection compared to ablation for single tumor diameter 3-5 cm
In the present study, we aimed to investigate the impact of SR and

| The treatment outcomes of SR and ablation therapy were influenced by the location of the tumor
The location of the tumor was considered when analyzing the treatment outcomes of SR and ablation therapy.Regarding tumors located in the central region (IV, V, VIII) of the liver, there was no statistically significant difference in OS between the SR and ablation groups (p = .064).However, SR was superior to ablation therapy in terms of RFS ( p = .0064).Regarding tumors located in the noncentral region (II, III, VI, and VII), there was no significant difference in OS or RFS between the two treatment groups ( p = .6774and p = .7094,respectively) (Figure 5).Furthermore, no significant differences in OS or RFS were observed between the SR and ablation groups for tumors located in the left lobe of the liver ( p = .2319and p = .9208,respectively).However, for tumors located in the right lobe of the liver, both OS and RFS were significantly better with SR than with ablation therapy (p = .0212and p = .0072,respectively) (Figure S2).F I G U R E 4 K-M curves comparing OS and RFS in different subgroups.(A, B) According to the subgroup analysis of patients with a solitary HCC lesion<3 cm, there were no significant differences in OS or RFS.(C, D) for patients with solitary HCC 3-5 cm, while the difference in OS between the two groups was not statistically significant, the RFS was better in the SR group than in the ablation group.HCC, hepatocellular carcinoma; OS, overall survival; RFS, recurrence-free survival; SR, surgical resection.
F I G U R E 5 K-M curves comparing OS and RFS in different subgroups.For tumors located in the central region of the liver, there was no statistically significant difference in OS between SR and ablation (A), however, SR was found to be superior to ablation therapy in terms of RFS (B).For tumors located in the noncentral region, there was no significant difference in OS (C) or RFS (D) between the two treatment groups.OS, overall survival; RFS, recurrence-free survival; SR, surgical resection; HCC, hepatocellular carcinoma.
above, an AFP concentration ≥ 400 ng/mL, and early recurrence significantly impacted OS ( p < .05).Additionally, multifactorial analysis confirmed that HBV infection, a tumor diameter ≥3 cm, an AFP concentration ≥ 400 ng/mL, and early recurrence were independent risk factors for poor OS ( p < .05)(Table 3).Moreover, univariate analysis revealed that ablation, a PLT < 100 Â 10 9 /L, satellite foci, and the presence of ascites before surgery were statistically significant factors affecting recurrence ( p < .05).The multifactorial analysis further confirmed that a PLT < 100 Â 10 9 /L, an ALBI grade 2 or above, and the presence of satellite foci were independent risk factors for recurrence (P < 0.05) (Table 4).

| DISCUSSION
HCC is the most prevalent primary liver malignancy, and recent advancements in surveillance efforts targeting individuals at high risk of developing HCC have led to an increase in the number of earlystage HCC diagnoses. 26Consequently, the accurate selection and optimization of initial treatment options have gained paramount importance in determining the prognosis of patients with early-stage HCC. 27  Our study revealed that, before PSM, compared to the surgical resection group, the ablation group had certain distinguishing characteristics.Specifically, patients in the ablation group were older and exhibited lower white blood cell, platelet, and albumin levels.Conversely, they exhibited higher levels of bilirubin and AST.Additionally, the ablation group had a greater proportion of patients classified as Child-Pugh grade B and having single tumors, albeit smaller in size.
These findings suggest that in clinical practice, patients with poorer liver function, compromised systemic conditions, and smaller tumor diameters are more likely to undergo ablation as a treatment modality.
Importantly, this treatment choice introduces a potential risk factor for recurrence and survival in patients with HCC, potentially having a substantial impact on the outcomes of our study.Balancing all variables after PSM increased the credibility of the study results.
During the perioperative period, ablation significantly reduced intraoperative bleeding and transfusion rates, and patients who underwent ablation had lower postoperative opioid analgesic use, shorter hospital stays and lower hospital costs than those who underwent resection.In terms of complications, SR patients had a significantly greater incidence of Grade II or above complications than did ablation patients.Although a few patients experienced more severe complications, such as bleeding, biliary leakage, pleural and abdominal effusion, and liver failure, these complications were effectively managed after aggressive treatment involving fluid rehydration and expansion, surgical suturing, and drainage of effusion fluid.These observations not only highlight the less invasive and traumatic nature of ablation but also underscore its superior short-term recovery outcomes in comparison to those of SR, generally aligning with existing reports. 28e's prospective study revealed no statistically significant difference in OS between hepatectomy and radiofrequency ablation (RFA) but indicated superior RFS. 23Similarly, Hung et al. and Wang et al.
yielded the same results. 22,24These studies have consistently reported comparable survival rates for SR and RFA in early-stage HCC, but significantly lower recurrence rates with SR than with RFA.
In our study, before and after PSM, patients with early-stage HCC and those who underwent resection and resection had similar survival outcomes.Nevertheless, patients who underwent SR had a more favorable RFS than those who underwent ablation.
Despite the superior RFS in the SR group compared with the ablation group, there was no difference in the final OS between the two groups.The favorable OS observed in both groups can be attributed to several factors.First, our study exclusively included patients with very early-stage or early-stage HCC according to the Barcelona staging system.Second, more than 90% of the enrolled patients had isolated tumors and relatively small tumor diameters.More than half of the patients had tumor diameters less than 2 cm, allowing for better ablation margins, including microsatellite nodules around the tumor. 29ditionally, more than 80% of patients had Child-Pugh class A tumors, indicating good liver function, and facilitating effective follow-up treatments.As mentioned in the study by Huang et al., 16 the disparity in RFS can be explained by the variance in tumor clearance achieved through the two treatments.HCC tumor cells primarily disseminate through the portal bloodstream, revealing why HCC frequently spreads within the same liver segment along portal branches. 16SR involves the thorough removal of segmental portal vein branches, effectively eliminating potential tumor emboli and the primary tumor within the same segment.Ablation of HCC tissue frequently necessitates multiple electrode insertions and ablations, presenting challenges in achieving fully overlapping ablations under 2D imaging guidance. 16,23This may be an important reason for the superior RFS rate of SRs compared with ablations.However, early tumor recurrence did result in increased hospital admissions and salvage treatment.In this study, most patients underwent a combination of treatments, including repeat liver resection, ablation, TACE, targeted therapy and immunotherapy with PD-1/PD-L1 inhibitors, more frequently after tumor recurrence, all of which may have affected the final survival outcomes observed in our study.
The diameter and number of tumors are crucial to the choice of clinical treatment, and treatment guidelines offer different recommendations based on these factors.Local ablation has been reported to be highly effective for patients with a tumor diameter less than 3 cm. 30cordingly, we categorized our patients into two subgroups: those with single tumors measuring less than 3 cm in diameter and those with single tumors ranging from 3 to 5 cm in diameter.1][12] Conversely, among patients with single tumors ranging from 3 to 5 cm in diameter, our results demonstrated that OS was comparable in both groups, but SR was significantly better than ablation in terms of RFS, which is generally consistent with the results of a retrospective study by Wang et al. 31 Notably, Wang et al.'s study revealed comparable DFS between the two treatment groups when compared to patients enrolled in later years, indicating that ablation could serve as a potential alternative to SR for 3-5 cm tumors when the technology matures.Zheng et al. reported that SR and ablation provided similar outcomes for patients with 3-5 cm long HCC lesions, but their study had a limited sample size. 32Therefore, further studies with larger sample sizes are needed regarding the treatment of 3-5 cm long HCC lesions.
The impact of tumor location on postoperative survival outcome in patients with HCC has attracted widespread attention in recent years, yet a consensus regarding treatment remains elusive.Based on the Couinaud classification of the liver, tumors located in segments IV, V and VIII of the liver are classified as the central type of HCC. 33ese tumors possess a unique anatomical location and present considerable surgical challenges due to their proximity to vital liver vessels, such as the portal vein, hepatic vein, and inferior vena cava.
Historically, SRs of central HCC patients have engendered serious complications, such as hemorrhage and liver failure, due to massive resection of the liver parenchyma, but the incidence of these serious complications has been substantially mitigated in recent years due to advancements in surgical techniques, approaches, and instruments.
Orimo et al. conducted an analysis comparing the efficacy of central hepatectomy and major hepatectomy for central HCC and reported no significant difference in short-or long-term survival rates or recurrence between the two approaches. 34Similarly, a meta-analysis yielded the same outcome, 35 with no difference in complications between the two treatments.Overall, the SR of central HCC was generally considered safe and dependable.A review of the literature revealed limited studies comparing the effectiveness of SR and ablation for central HCC.
Thus, in this study, we undertook a separate comparison of SR and ablation for central and noncentral HCC patients to assess their respective efficacies.The results showed that there was no significant difference in OS between SR and ablation for central HCC, while SR was associated with a lower recurrence rate than ablation.However, in noncentral HCC patients, there was no difference in OS or RFS between the two groups.The disparity in outcomes can be attributed to several factors.First, HCC located in the central region is challenging due to its deep location and difficulty in localization.Percutaneous ablation requires caution to avoid damage to adjacent blood vessels, potentially resulting in incomplete ablation.Moreover, the proximity of the tumor to large blood vessels can cause a heat sink effect, substantially diminishing the effectiveness of coagulative necrosis and thereby impacting the outcome. 36In addition, patients with lesions located in the right lobe of the liver exhibited longer long-term OS and RFS when treated with SR than when treated with ablation.The segmental distribution of HCC has been previously reported to be proportional to the volume of the liver lobe or other lobes. 37In this study, a high incidence of HCC was observed in the right lobe of the liver (74.3%), mainly in hepatic segments V, VII and VIII, consistent with the findings reported by Renzulli et al. 38 Tumor location in segment VIII, which is proximal to the diaphragm, was identified as an important factor influencing the effectiveness of ablation, and location in this segment was associated with a 3.5-fold greater risk of microvascular invasion (MVI) than location in other liver segments.Notably, local recurrence of HCC in segments VII and VIII occurred after ablation.The proximity to the diaphragm was an independent predictor of local recurrence after ablation, as positioning the ablation probe was more difficult. 39e recurrence rate of HCC following SR remains high, significantly impacting patient survival and prognosis.Studies have reported a recurrence rate of 50-70% at 5 years postsurgery. 40 AFP is a widely used serum tumor indicator in clinical HCC diagnosis, 42 and previous studies have confirmed that AFP can promote cancer cell proliferation, motility, invasive growth, and metastasis in various HCC cell lines or animal models. 43In this study, a preoperative AFP concentration ≥ 400 ng/mL was identified as a risk factor for shorter OS after surgery, although no statistically significant differences were observed in terms of recurrence.Liver function status represents an important preoperative assessment in HCC patients and is closely related to the occurrence of liver failure during the perioperative period and the postoperative prognosis.The ALBI grade is an index used to evaluate liver reserve function, with a higher ALBI grade representing poorer liver function.A study revealed that the ALBI grade was strongly correlated with patient prognosis and had a greater predictive value than the Child-Pugh grade. 44Therefore, we included the ALBI grade in the Cox regression analysis, and a high ALBI grade was found to be an independent risk factor for both survival and recurrence.Platelets are used mainly for hemostasis after vascular injury, and in recent years, some studies have demonstrated that platelets may play a role in the hematogenous metastasis of HCC.With respect to the prognosis after hepatectomy, some researchers have found that thrombocytopenia is a risk factor for the recurrence of HCC after surgery. 45Our study obtained similar results, although the exact mechanism remains unknown.Platelets may promote liver regeneration and the growth of HCC cells, warranting further investigation.Satellite foci around tumor nodes in HCC are caused mainly by intrahepatic metastases, reflecting the aggressiveness of the tumor.In the present study, satellite foci were identified as an independent risk factor for the recurrence of HCC after surgery, consistent with the findings of recent studies and expert consensus.
Donat et al. also reported 5-year recurrence rates of 37.5% and 16.8% for HCC patients with and without satellite foci, respectively. 46is study has inherent limitations.As a single-center study, this study inevitably introduced potential selection and indication biases.
Given that the study was retrospective, there may have been loss to follow-up during the follow-up process.Despite some minor limitations, this clinical study has notable strengths, rendering it valuable.In recognition of its single-center retrospective cohort design, PSM was implemented to alleviate the impact of confounding and selection bias.Furthermore, we compared treatment outcomes for patients with tumors of varying diameters and locations and followed up for a longer period of time, contributing valuable insights to guide clinical treatment decisions.

| CONCLUSION
In conclusion, this study serves as a valuable foundation for the application of ablation in the management of early-stage HCC.The minimally invasive nature of ablation provides important advantages, positioning it for wider application in the treatment of HCC patients with a tumor size less than 3 cm.However, it is worth noting that over 90% of the patients included in this study had isolated tumors.Thus, further research and analysis are warranted to ascertain whether the results are the same for patients with multiple small HCC lesions.

3. 7 |
Risk factors impact the survival and recurrence rate of HCC patientsCox proportional hazard models were constructed in this study utilizing univariate and multivariate analyses that incorporated various variables, including surgical modality, age, sex, ALBI grade of liver function, tumor diameter, number of tumors, cirrhosis, and alphafetoprotein (AFP) levels.The results from the univariate analysis indicated that HBV infection, a tumor diameter ≥3 cm, an ALBI grade 2 or F I G U R E 3 K-M curves comparing RFS.(A) In the total cohort, the 5-year RFS rates were 60.0% for SR and 51.4% for ablation, respectively.(B) After PSM, the 5-year RFS rates were 62.9% for SR and 54.0% for ablation.PSM, propensity score matching; RFS, recurrence-free survival; SR, surgical resection.
outcomes.Considering this research gap, the objective of the present study was to conduct a single-center retrospective cohort study to compare the efficacy of SR and ablation techniques for managing early-stage HCC.
Addressing postoperative recurrence and improving survival have become prominent research foci.Numerous studies have demonstrated several high-risk factors for postoperative recurrence and survival, including large tumor size, multiple tumors or satellite foci, tumor envelope invasion or absence, MVI, and high AFP levels.41In our study, HBV infection, tumor diameter ≥3 cm, early recurrence, and AFP≥400 ng/ mL were identified as independent risk for low OS; PLT < 100 Â 10 9 / L, ALBI grade 2 or above, and satellite foci were independent risk factors for recurrence.Surgery-induced immunosuppression has been associated with an increased risk of HBV reactivation, leading to cirrhosis or the accelerated progression of preexisting cirrhosis and ultimately resulting in HCC recurrence.Routine postoperative treatment with antiviral drugs effectively inhibits HBV reactivation and reduces the level of inflammation in the residual liver, delaying the progression of cirrhosis or liver failure to some extent.Tumor size not only correlates with invasive and metastatic potential but also affects the difficulty of treatment.Larger tumors pose challenges during surgery, increase postoperative liver burden, and increase the risk of liver failure.In ablation approaches, a larger tumor diameter requires repeated insertion and ablation, making it difficult to accurately cover the entire liver area in three dimensions under the guidance of twodimensional ultrasound and possibly leading to incomplete ablation or the risk of needle tract metastasis,17 which favor a poor prognosis.